Complement activation and atherosclerosis

Atherosclerosis is an inflammatory disease mediated through the action of m onocyte/macrophages, complement and T-lymphocytes. C5a and monocyte chemota ctic factor released during complement activation in the arterial wall may participate in the initial monocyte recruitment. Assembly of C5b-9 on cells of the arterial wall may also induce cell lysis. On the other hand, sublyt ic assembly of C5b-9 on smooth muscle cells (SMC) and endothelial cells (EC ) induces cell activation and proliferation. Analysis of mitogen activated protein kinases (MAPK) pathways induced by C5b-9 in aortic SMC revealed tha t extracellular signal regulated kinase (ERK) 1, c-jun NH2-terminal kinase (JNK) 1, and p38 MAPK are all activated by C5b-9. ERK1 activity was inhibit ed by wortmannin suggesting that ERK1 pathway is activated through phosphat idyl inositol -3 (PI 3-) kinase. Sublytic C5b-9 assembly on the plasma memb rane was also able to activate Janus kinase (JAK) 1, signal transducer and activator (STAT) 3 and STAT4 in EC. JAK1 but not STAT3 activation induced b y C5b-9 is dependent on Gi protein activation. New evidence accumulated dur ing the last decade support the role of complement activation in both initi ation and progression of the atherosclerotic lesions. Complement system act ivation is a major component of the chronic inflammatory process associated with atherosclerosis. (C) 1999 Elsevier Science Ltd. All rights reserved.